Steroidogenic Acute Regulatory (StAR)-Directed Immunotherapy Protects against Tumor Growth of StAR-Expressing Sp2-0 Cells in a Rodent Adrenocortical Carcinoma Model

Abstract

Adrenocortical carcinoma (ACC) is a highly malignant tumor with poor response to classical antitumor therapy. Steroidogenic acute regulatory (StAR) protein is expressed in most human ACCs. The aim of this study was to induce antitumoral T cells directed against StAR in a murine tumor model. Because a suitable syngenic adrenocortical mouse tumor model is lacking, we established a clone of the mouse myeloma Sp2-0 tumor cell line stably expressing murine StAR (Sp2-mStAR). Using repeated im injections of plasmid DNA encoding mStAR followed by infection with a recombinant vaccinia virus (rVV) expressing mStAR, we induced a cytotoxic T-cell response as measured by enzyme-linked immunospot assay. To demonstrate antitumor activity of the vaccination procedure, mice were treated as follows: group A, mice immunized with plasmids and rVV encoding mStAR receiving Sp2-mStAR cells; control group B, mice immunized with the empty plasmid and the empty rVV receiving Sp2-mStAR cells; control group C, mice immunized with the empty plasmid and rVV encoding P450 side-chain cleavage enzyme receiving Sp2-mStAR cells; and control group D, mice immunized with plasmid and rVV encoding mStAR receiving parental Sp2-0 cells. A high proportion (89-100%) of the control groups B, C, and D developed subcutaneous tumors. In contrast, immunization specific for mStAR (group A) was highly protective against tumor growth (percentage of tumor-free animals, 67%; P < 0.001 vs. controls). In summary, these results show that T-cell tolerance toward mStAR can be broken, resulting in antitumoral immunity. Thus, StAR represents a candidate target antigen for immunotherapeutic strategies against ACC.

Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma

“…The main obstacle for an effective immunotherapy is that no established tumour antigen has yet been identified for ACC. Recently, an approach in a murine model gave evidence that steroidogenic acute regulatory protein (StAR) potentially serves as an immunotherapeutic target 37 . But StAR is present only in a subset of patients with ACC 38 .…”

“…Recently, an approach in a murine model gave evidence that steroidogenic acute regulatory protein (StAR) potentially serves as an immunotherapeutic target. 37 But StAR is present only in a subset of patients with ACC. 38 We therefore used whole TL as antigen source in our study.…”

The challenge of developmental therapeutics for adrenocortical carcinoma

“…Based on the wide expression of the steroidogenic acute regulatory protein (StAR) in adrenal tissue and ACC cell models, a specific immune response against this antigen was elicited using an immunization protocol with DNA plasmids and recombinant vaccinia virus vectors and resulted in an anti-tumor effect in a xenograft model utilizing tumor cell line expressing StAR. [122–125] Another study describing vaccination of two patients with metastatic ACC using autologous dendritic cells pulsed with autologous tumor lysate showed tumor-specific immune response in spite of excessive production of glucocorticoids by the tumor. [126] The anti-neoplastic activity resulting from immunotherapy strategies ( e.g., checkpoint inhibitors anti-CTLA-4 and anti-PD-1 antibodies) for the treatment of solid tumors such as melanoma and non-small cell lung cancer has driven the interest to explore its potential clinical efficacy in ACC.…”

Current and Emerging Therapeutic Options in Adrenocortical Cancer Treatment

“…However, no clinical advantage was observed [93, 129]. The main limitation of this therapy is the difficulty in identifying specific tumoral antigens; however some interesting targets for a specific immunotherapeutic approach in ACC might be represented by steroidogenic factor 1, surviving and steroidogenic acute regulatory protein (StAR) [94, 130]. …”